Common genetic variants associated with urinary phthalate levels in children: A genome-wide study

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  • dc.contributor.author Bustamante Pineda, Mariona
  • dc.contributor.author Balagué-Dobón, Laura
  • dc.contributor.author Casas Sanahuja, Maribel
  • dc.contributor.author Maitre, Léa
  • dc.contributor.author Nurtdinov, Ramil
  • dc.contributor.author González, Juan Ramón
  • dc.contributor.author Vrijheid, Martine
  • dc.date.accessioned 2024-09-20T06:06:37Z
  • dc.date.available 2024-09-20T06:06:37Z
  • dc.date.issued 2024
  • dc.description.abstract Introduction: Phthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes. Objective: In this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS). Methods: The study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void pooled urine collected at the mean age of 8 years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value < 1E-05) was done with the FUMA web-tool. Results: We identified four genome-wide significant (p-value < 5E-08) loci at chromosome (chr) 3 (FECHP1 for oxo-MiNP_oh-MiNP ratio), chr6 (SLC17A1 for MECPP_MEHHP ratio), chr9 (RAPGEF1 for MBzP), and chr10 (CYP2C9 for MECPP_MEHHP ratio). Moreover, 115 additional loci were found at suggestive significance (p-value < 1E-05). Two CNVs located at chr11 (MRGPRX1 for oh-MiNP and SLC35F2 for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion. Conclusion: Through genome-wide screenings we identified known and novel loci implicated in phthalate metabolism in children. Genes annotated to these loci participate in detoxification, transmembrane transfer, and renal excretion.
  • dc.description.sponsorship The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project) and the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). The genotyping was supported by the project PI17/01225 and PI17/01935, funded by the Instituto de Salud Carlos III and co-funded by European Union (ERDF, “A way to make Europe”) and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1), and National Institute for Health Research Applied Research Collaboration Yorkshire and Humber (NIHR200166). The views expressed are those of the author(s), and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. CRG acknowledge the support of the Spanish Ministry of Science, Innovation, and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. LM is funded by a Juan de la Cierva-Incorporación fellowship (IJC2018-035394-I) awarded by the Spanish Ministerio de Economía, Industria y Competitividad. MC holds a Miguel Servet fellowship (MS16/00128) funded by Instituto de Salud Carlos III and co-funded by European Social Fund “Investing in your future”.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Bustamante M, Balagué-Dobón L, Buko Z, Sakhi AK, Casas M, Maitre L, et al. Common genetic variants associated with urinary phthalate levels in children: A genome-wide study. Environ Int. 2024 Aug;190:108845. DOI: 10.1016/j.envint.2024.108845
  • dc.identifier.doi http://dx.doi.org/10.1016/j.envint.2024.108845
  • dc.identifier.issn 0160-4120
  • dc.identifier.uri http://hdl.handle.net/10230/61185
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.ispartof Environ Int. 2024 Aug;190:108845
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/308333
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/874583
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/211250
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/226285
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2018-000806-S
  • dc.rights © 2024 Barcelona Global Health Institute. Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
  • dc.subject.keyword Copy number variant (CNV)
  • dc.subject.keyword Genetic variant
  • dc.subject.keyword Genome-wide association study (GWAS)
  • dc.subject.keyword Metabolism
  • dc.subject.keyword Phase I and II enzymes
  • dc.subject.keyword Phthalate
  • dc.subject.keyword Renal excretion
  • dc.subject.keyword Single nucleotide polymorphism (SNP)
  • dc.subject.keyword Toxicity
  • dc.title Common genetic variants associated with urinary phthalate levels in children: A genome-wide study
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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